When antibiotics are orally administered, they are usually absorbed by the host in the upper parts of the intestinal tract, such as the duodenum or the jejunum. If the administered dose is not completely adsorbed, it travels further along the intestinal tract, through the ileum and the colon. The portion of the dose that is absorbed reaches the blood stream and, depending on the particular pharmacokinetics of the antibiotic, is excreted through the liver through the bile and back in the intestinal tract in either an active form or an inactive form, depending on the metabolism that has occurred in the liver.
The active metabolites reach the ileum and the colon around the same time as the portion of the antibiotic dose that has not been absorbed, as described above. When antibiotics are administered parenterally, part of the administered dose can, however, reach the intestinal tract through biliary excretion, just as the absorbed fraction of an antibiotic administered orally. Whether the antibiotics have been administered orally or parenterally, there is thus a noticeable fraction of the administered dose that reaches the colon in an active form, where it comes into contact with the numerous commensal bacterial populations within the colon of all living species.
The result is the production of commensal bacteria that are resistant to the antibiotic administered and, often, to many other antibiotics, because the resistance mechanisms to various antibiotics are often physically linked on genetic elements such as plasmids and integrons and thus can be selected by a single antibiotic pressure.
As a result of this process, the patient, or the animal, that has received the antibiotic treatment becomes highly colonized by antibiotic-resistant bacteria, and this can result in further infection by resistant bacteria, and the dissemination of such resistant bacteria in the environment. It is now widely accepted that the selection and dissemination of such resistant bacteria is a major factor that speeds up the dissemination of bacterial resistance to antibiotics both in the community and in the hospitals. Levels of bacterial resistance are currently extremely high, and this is a major public health problem worldwide that could lead to major outbreaks of infections very difficult to treat with available antibiotics either in humans or in animals.
Besides producing antibiotic-resistant bacteria, antibiotics that reach the colon in active form will also profoundly alter the composition of the commensal flora and kill the susceptible species. Among those are often present anaerobic bacteria that have a major physiological role in the intestine of normal subjects and animals, i.e. that of preventing colonization by exogenous potentially pathogenic microorganisms such as Clostridium difficile and/or Candida sp, and/or multiresistant exogenous bacteria such as Vancomycin-resistant enterococci. Thus, resistance to colonization by such potential pathogens is often reduced during antibiotic treatments. This can lead to the appearance of pathologic signs and symptoms, such as post-antibiotic diarrhea or the more severe forms of pseudomembranous colitis, Candida genital infections, particularly in women, or antibiotic-resistant systemic infections in hospitalized patients, particularly patients in intensive care.
In the past, there have been two different approaches, specific and general, for reducing the above mentioned effects of antibiotics on the colonic flora during treatments. A specific approach has been to use enzymes that specifically destroy residual antibiotics in the lower part of the intestine before they can alter the colonic microflora of the treated subjects. This approach is described, for example, in U.S. Application Publication Number 2005/0249716, and can prevent the deleterious effects of beta-lactam antibiotics as well as other antibiotic families, such as the macrolides and the quinolones. A potential limitation of this approach is that the required enzymes or combination of enzymes are sometimes difficult and expensive to produce on large scales, and are only active against a selected class of antibiotic molecules, often against only some of the representatives of this class. That is, the enzymes can inhibit some beta-lactams, or some macrolides, but not all of them. Also, since enzymes are proteins, they tend to be labile, difficult to formulate, and rapidly degraded in the upper part of the intestinal tract by the proteolytic activity found in normal intestinal juices.
It can further be important that the enzymes are not released too early in the intestine, or they will degrade antibiotics before they are significantly absorbed, potentially leading to a decreased activity of the antibiotic treatment. Along a similar line, there have been warnings that the administration of adsorbent materials, such as charcoal, at the same time as antibiotics, can also lead to a decreased efficacy of the antibiotic treatments.
It is worthy of note that antibiotic use in farm animals by far exceeds that in humans, and is a major driving force in the general evolution and dissemination of bacterial resistance to antibiotics.
It would be advantageous to provide additional compositions and methods of treatment for removing excess antibiotics and their metabolites from the intestinal tract, in order to reduce undesirable side effects such as diarrhea and the development of antibacterial-resistant bacteria without changing the fate of absorption on the antibiotic and its potential to treat the infection for which it had been administered. The present invention provides such compositions and methods of treatment.